Dementia refers to a progressive decline in memory and cognitive functioning that interferes with daily life, and may be largely divided into vascular dementia and Alzheimer's disease. Vascular dementia mainly corresponds to the case where stroke or cerebral infarction, etc. occurs by thrombus formed in blood vessels, and is known to be the onset of symptoms such as memory loss, etc. caused by damage to neighboring brain cells. On the other hand, Alzheimer's disease (AD), which accounts for a significantly greater part of dementia than vascular dementia, is a progressive brain disorder that slowly weakens memory, changes personality, and destroys thinking skills. Most patients of Alzheimer's disease die of pneumonia, etc. within 8 to 10 years. Worldwide, 3.5 to 10% of the elderly people over the age of 65 suffer from this disease, and there are an estimated 4 million patients only in the US. Social costs incurred to treat this disease reach US$100 billion every year only in the US, making Alzheimer's disease a signature disease of old age.
The pathogenesis of Alzheimer's disease known until now is liberating β-amyloid from amyloid precursor protein (APP), generating insoluble amyloid plaque by having the liberated β-amyloid cohered, causing degeneration of neural cells by cohesion of β-amyloid and generation of amyloid plaques, and inducing generation of secondary neurofibrillary tangle as a result. As such, it has been found out that the accumulation of β-amyloid in brain tissue and neural toxicity accompanied therefrom activate as very important causes of Alzheimer's disease, and accordingly, research is focused on substances, like BACE-1 inhibitor, that have an effect of inhibiting the generation of β-amyloid, inhibiting cohesion, or inhibiting toxicity, which having less side effects, over the world. β-amyloid is a fragment of amyloid precursor protein generated when APP, an amyloid precursor protein, receives proteolytic enzymes such as gamma-secretase and beta-secretase. The beta-secretase enzyme which plays the most important role in generating β-amyloid is generally referred to as BACE, and two types of BACE, i.e., BACE-1 and BACE-2, etc. are known. Among them, BACE-1 has most activity (about 90%) of beta-secretase, and thus is known to play a much more important role than BACE-2 in generating β-amyloid.
Also, according to recent epidemiologic studies, it has been reported that risk factors for cerebrovascular diseases such as high blood pressure, diabetes, hyperlipidemia and cardiac disorders have increased the occurrence of Alzheimer's disease as well as vascular dementia. From the modern medical point of view on cognitive impairment caused by Alzheimer's disease (AD), extensive degeneration and loss of cholinergic neurons in the brain are considered as the leading cause of cognitive decline, and as a means to overcome this problem, most studies aim to develop drugs that can partly recover impaired cognitive functioning by increasing the activity of the cholinergic nervous system left undamaged.
Recently, four drugs (tacrine, rivastigmine, donepezil, and galantamine) have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer's disease, and they are all so-called acetylcholinesterase inhibitors which intend to dramatically improve cognitive functioning by inhibiting the activity of acetylcholinesterase enzymes. Until now, acetylcholinesterase inhibitors are the only drugs approved as a therapeutic agent of Alzheimer disease. However, these drugs have disadvantages such that they only present a temporary relief of symptoms in some Alzheimer's patients (40-50%), and the efficacy does not last long. Also, although the drug has to be taken for a long period of time due to the characteristic of the disease, the acetylcholinesterase inhibitors developed until now had problems such that they accompanied a number of side effects including liver toxicity. That is, the therapeutic agents developed until now only temporarily relieved the symptoms, and thus development of drugs fundamentally treating the disease or inhibiting the progress of the disease is urgently required.
Meanwhile, sphingolipid metabolism controls signal transduction of normal cells, and ASM, an enzyme controlling sphingolipid metabolism, is a protein expressed in almost all cell types, and has an important role in sphingolipid metabolism and membrane turnover. The ASM is mainly located within the endosomal/lysosomal compartment, and when there is a cellular stress response, it is transported outside the cell membrane. ASM increases in various diseases such as Wilson's disease, diabetes, cystic fibrosis, emphysema, etc., and may have a significant correlation with the onset of the diseases. However, despite the above role of ASM, currently there is little progress in studies on the relationship between ASM and Alzheimer's disease.
In this regard, the present inventors found ASM as a pathogenesis of Alzheimer's disease and completed the present invention by confirming that when ASM is partially removed in an Alzheimer's disease model mouse, that is when ASM is inhibited therein, such as when an Alzheimer's disease model mouse with a partial removal of ASM is in a parabionic union with an Alzheimer's disease model mouse, or when an Alzheimer's disease model mouse is injected with the serum of an Alzheimer's disease model mouse from which ASM gene has been removed, the deposition of β-amyloid in the brain tissue is inhibited and the ability to learn and remember is improved.